Abstract
Objective: To devise a staging scheme for addressing the severity of atrophy in patients with pathologically proven frontotemporal dementia (FTD) and determine any relationship with clinical indices.
Methods: Twenty-four cases with clinical and pathologic features of FTD were selected using standard inclusion and exclusion criteria from 125 dementia cases collected in Sydney, Australia, over an 8.5-year period. Patterns of gross atrophy were determined in two coronal brain slices. Reproducibility of a four-stage severity scheme was tested. Nonparametric statistics were used to determine relationships between the stage of atrophy and clinical indices (age at death, duration from diagnosis, and clinical severity at death).
Results: The FTD cases studied could be reliably grouped (κ = 0.97) into four progressively severe stages of global atrophy. Initial mild atrophy occurred in the orbital and superior medial frontal cortices and hippocampus (stage 1), progressed to involve the other anterior frontal regions, temporal cortices, and basal ganglia (stage 2), then involved all remaining tissue in these coronal slices (stage 3), until very marked atrophy was observed in all areas (stage 4). These stages correlated with disease duration and clinical dementia severity, lending validity to the progressive nature of the staging scheme.
Conclusions: The authors have identified a reproducible staging system for the severity of gross atrophy in cases of FTD. This staging scheme provides the required framework to compare different research indices and determine correlates relating to time and disease progression in FTD—information necessary to determine core disease processes and etiologic factors.
Frontotemporal dementia (FTD) is the second most common neurodegenerative disease resulting in dementia in patients younger than 65 years.1 Multiple neuropathologic changes underlie more homogenous clinical presentations of this disorder.2-4⇓⇓ Current research on FTD has focused largely on pathogenesis, clinical phenomenology, and differentiation from other dementia syndromes.
Whereas there are reports documenting the clinical progression of FTD disorders in individual cases, the neuropathologic staging or progression of disease is poorly understood. In other degenerative conditions, severity staging of key pathologic indices has considerably advanced correlative studies and has proven to be an adequate surrogate for disease progression.5,6⇓ In FTD, all cases demonstrate macroscopic changes in frontal and anterior temporal regions,2,3⇓ with variable atrophy of other gray and white matter structures. We present a new schema for staging the severity of such macroscopic atrophy in order to understand the relationship of this key neuropathologic feature to the clinical and pathologic disease processes.
Methods.
Cases.
Cases were selected from a neuropathologic series of 125 patients with dementia collected from a brain donor program in Sydney, Australia, between October 1993 and February 2002. Only cases with full medical records detailing their clinical history were included. In particular, we included patients who underwent regular follow-up even after entry into nursing home care. The study was approved by the Human Ethics Committees of the Universities of Sydney and New South Wales. Brains were removed at autopsy (mean postmortem delay ± SD was 18 ± 17 hours, range 2 to 72 hours), and the entire brain fixed by suspension in 15% buffered formalin for 2 weeks. The brains were then weighed, the antero-posterior dimensions recorded, and the brainstem and cerebellum separated from the cerebrum at the level of the superior colliculus. The cerebrum was embedded in agar and cut into 3-mm–thick coronal slices using a rotary slicer. The brainstem was embedded in agar and similarly cut into 3-mm–thick slices in the transverse plane, as previously described.7 Each slice was photographed and printed at one times magnification for the assessment of gross atrophy.
Tissue samples were prepared for routine neuropathologic examination. Briefly, samples were taken from the frontal (Brodmann area 9), temporal (area 20), parietal (area 39), occipital (areas 17 and 18), and anterior cingulate (area 24) cortices, as well as from the hippocampus at the level of the lateral geniculate nucleus, amygdala, anterior and posterior basal ganglia (including the basal forebrain), thalamus, hypothalamus, midbrain, pons, medulla oblongata, and cerebellum. These were embedded in paraffin and sectioned at 10 μm. Sections from all regions were stained for routine screening using currently recommended diagnostic protocols for AD,8 dementia with Lewy bodies,9 Pick disease,2 corticobasal degeneration (CBD),10 progressive supranuclear palsy,10 and multiple system atrophy.11 Standard stains used included hematoxylin and eosin, Congo red, and the modified Bielschowsky silver stain; immunohistochemistry was performed using antibodies against ubiquitin (Z0458, Dako, Glostrup, Denmark, diluted 1:200), tau II (T5530, Sigma, St. Louis, MO, diluted 1:10,000), and α-synuclein (18–0215, Zymed Laboratories Inc., San Francisco, Ca, diluted 1:200). Cases were excluded if they met pathologic criteria for AD,8 dementia with Lewy bodies,9 or CBD,10 or had macroscopic infarction or substantial subcortical pathologies, such as multiple system atrophy11 or progressive supranuclear palsy.10 This resulted in 24 cases for analysis.
Seventeen of the 24 cases had no family history of dementia or other neurologic condition. Four of these cases tested negative for tau gene abnormalities (no genetic screening tests were found in the medical records of the remaining cases). Seven of the 24 cases had family members with dementia or motoneuron disease. Five of these cases had an affected parent and were negative on tau gene mutation screening tests. The other two cases had siblings and a grandparent with dementia but had negative tau gene screening tests.
Neuropathologic classification.
Cases were classified into two groups according to the presence or absence of tau-immunoreactive inclusions.
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Tau-positive FTD—11 of 24 cases had FTD with silver- and tau-positive Pick bodies in the cerebral cortex, amygdala, or hippocampus. No other cases had tau-positive inclusions.
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Tau-negative FTD—10 of 24 cases had FTD with neuronal loss, gliosis, and vacuolation in frontal and temporal cortices, but no silver-, tau-, or ubiquitin-positive intraneuronal inclusions or pathology (frontotemporal lobar degeneration). Three of 24 cases had FTD with coexisting motor neuron disease and ubiquitin-positive, tau-negative inclusions in brainstem motor nuclei and the hippocampus (FTD-MND).
Clinical classification and assessment of clinical severity.
A retrospective review of the full medical records was conducted by a behavioral neurologist with longstanding expertise in the dementias (J.R.H.) who was unaware of the pathologic diagnosis or rating of severity. Particular attention was paid to the first clinical assessment and diagnosis by the neurologist or geriatrician, the date of diagnosis, and onset of symptoms as reported by the family (there was a discrepancy of up to 10 years).
For this study, we classified the main clinical syndrome using a modification of the consensus criteria for frontotemporal lobar degeneration12 that identifies the behavioral variant, semantic dementia, and progressive nonfluent aphasia of FTD. In keeping with prior publications by the Cambridge group, we prefer the terms frontal or behavioral variant FTD, semantic dementia, and progressive nonfluent aphasia. In addition, two other clinical categories (FTD-MND and CBD) were included in the classification, as these have been incorporated into the rubric of FTD syndromes and show considerable clinical overlap with other syndromes.2,13,14⇓⇓ Patients were classified with FTD-MND if they presented with behavioral changes and developed bulbar symptoms accompanied by fasciculation within 12 months. Patients were classified with CBD if their main symptoms were limb apraxia with gait disturbance and parkinsonism.15,16⇓
Severity of dementia at death was assessed using the extended version of the original Clinical Dementia Rating (CDR)17 as follows:
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Mild: cognitive and behavioral symptoms but still capable of managing household tasks and no problems with self-care.
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Moderate: more substantial cognitive deficit, requiring some help with activities of daily living and with self-care.
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Severe: no notable function in the home, requiring help with all aspects of self-care but able to walk unaided, some speech and occasional incontinence only.
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Profound: unable to follow command or mute, eats with fingers, incontinent most of the time, able to walk a few steps with help, chairbound.
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Terminal: no verbal response or communication, needs feeding or has feeding tube, total incontinence, bedridden, unable to sit or stand.
Statistical correlations.
The reproducibility of rating gross atrophy into four different stages was tested using data from three independent researchers blind to case details and κ statistics for multiple raters.18 Published guidelines for interpreting the κ values were used19: 0.00 to 0.20 = slight agreement, 0.21 to 0.40 = fair agreement, 0.41 to 0.60 = moderate agreement, 0.61 to 0.80 = substantial agreement, 0.81 to 1.00 = almost perfect to perfect agreement.
Statview (Abacus, Berkeley, CA) was used to calculate all other statistical analyses. Means and SD were calculated for all variables and a p value of < 0.05 taken as the level of significance. Linear regression analyses were used to determine any relationships between similar clinical variables, whereas differences between the pathologic groups in these clinical measures were tested using unpaired t-tests or exact tests. To determine any relationships between variables (pathologic stage, clinical severity, age at death, and disease duration from diagnosis), Spearman rank correlations were performed.
Results.
Staging the severity of gross patterns of atrophy.
There was considerable variability in the degree of gross brain atrophy between cases. Standard brain slices were selected for the evaluation of regional gross atrophy. This procedure is similar to that developed for Huntington disease (HD),5 a disease where there is also considerable variability in gross atrophy. Three standard coronal photographs approximately equidistant through the brain were selected and the side with the most marked atrophy analyzed. The coronal levels chosen were as follows:
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Level 1: the frontal lobe at the level containing the temporal pole including frontal, temporal, and orbitofrontal cortices and white matter, basal ganglia (incorporating the head of the caudate and putamen), the anterior horn of the lateral ventricle, and the corpus callosum (figure 1A).
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Level 2: the hippocampus at the level of the lateral geniculate nucleus including posterior frontal and temporal cortices and white matter, thalamus, hippocampus, the body and inferior horn of the lateral ventricle, and corpus callosum (see figure 1B).
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Level 3: the occipital lobe containing the anterior primary visual cortex, a region relatively well preserved in cases with FTD (see figure 1C).
⇓For the most atrophic hemisphere in each case, a relative severity rating was given based on the degree of gross brain atrophy incorporating both gray and white matter changes. Cases fell into four progressively severe, characteristic stages of global atrophy (stages 1 to 4, figure 2). Asymmetric involvement was noted in two cases (figure 3). The posterior coronal section (anterior occipital lobe) did not provide any additional staging information compared with the two anterior coronal sections and was therefore omitted from the staging scheme as described below.
Figure 1. Photographs of coronal brain slices show the internal landmarks used to verify the correct antero-posterior level analyzed for the staging scheme. (A) Level 1 was taken in the frontal lobe at the level containing the temporal pole (TP). It includes the anterior superior frontal (SF) and orbitofrontal (OF) cortices and white matter and basal ganglia, incorporating the head of the caudate (Ca) and putamen (Put), the anterior horn of the lateral ventricle (V), and the corpus callosum (CC). (B) Level 2 was taken through the hippocampus at the level of the lateral geniculate nucleus (LGN). It includes the posterior SF and temporal (PT) cortices and white matter, thalamus, hippocampus (under asterisk), the body (V) and inferior horn (asterisk) of the lateral ventricle, and CC. (C) Level 3 was sampled in that part of the occipital lobe containing the anterior primary visual cortex (Vis), which is a region relatively well-preserved in cases of FTD. This coronal section did not provide any staging information additional to that provided from the two anterior slices, and was therefore omitted from the staging scheme.
Figure 2. Half-brain coronal slices show the distribution of atrophy in representative cases in each stage of the scheme. Each stage is represented by coronal slices at the diagnostic levels 1 (top) and 2 (bottom) as detailed in figure 1. (A) Cortical slices in a neurologically and neuropathologically normal control for comparison against the progressive FTD atrophy noted in stages 1 to 4 (B through E). (B) At stage 1, there is mild atrophy of the orbital and superior medial frontal cortex and hippocampus. (C) By stage 2, additional atrophy of the remaining anterior frontal cortex, the temporal pole, and posterior and inferior temporal cortices is seen, as well as progression of atrophy in the superior medial frontal cortex and hippocampus. Atrophy of the basal ganglia is now observed, as structures become flattened, leading to dilatation of the lateral ventricle both anteriorly and posteriorly. (D) By stage 3, there is gross atrophy of the orbital and superior medial frontal cortex and hippocampus. The hippocampus now sits at the medial tip of the ventricle. There is progression of temporal and frontal lobe atrophy and associated white matter atrophy with substantial dilatation of the lateral ventricle both anteriorly and posteriorly and thinning of the corpus callosum. The basal ganglia is further degenerated, evident by a concavity of the ventricular surface. (E) Stage 4 cases had severe global atrophy, most notable by the dramatic loss of the basal ganglia. The ventricle is consequently concave and grossly dilated. The thalamus is reduced in size, and tapered along the lateral edge. The hippocampus is extremely small and temporal cortex and white matter are almost completely atrophied, although there is some preservation of the superior temporal gyrus.
Figure 3. Asymmetric atrophy of structures was noted in two stage 3 cases presenting with behavioral variant FTD (A, B; left is left, right is right). Coronal slices are shown at the diagnostic levels 1 (top) and 2 (bottom) as detailed in figure 1. For analysis, the staging of all cases was performed on the side with the most marked atrophy, which, for both cases, is the right side of the coronal slices. Both cases have more severe involvement of the right temporal cortices. Accompanying this atrophy is more severe involvement of the right orbitofrontal cortex and widening of the inferior horn of the lateral ventricle. In addition, there is more marked right-sided atrophy of the anterior cingulate and superior frontal cortices, as well as dilatation of the anterior horn of the lateral ventricle. The right lateral sulcus appears wider in case A, with concomitant loss of both gray and white matter of the superior temporal gyrus.
Stage 1 (see figure 2B) cases had mild but consistent atrophy of the orbital and superior medial frontal cortex and hippocampus as evident by slight enlargement of the temporal horn of the lateral ventricle. Other structures within these slices are preserved.
Stage 2 (see figure 2C) cases had additional atrophy of the remaining anterior frontal cortex, temporal pole, inferior temporal cortices, and basal ganglia (flattened ventricular surface) together with progression of the orbital and superior medial frontal cortical and hippocampal atrophy. The lateral ventricle is dilated both anteriorly and posteriorly. There is an obvious gap between the temporal pole and the inferior frontal lobe.
Stage 3 (see figure 2D) cases were distinguished most clearly from stage 2 by the gross atrophy of the orbital and superior medial frontal cortex and hippocampus. The hippocampus now sits at the medial tip of the temporal horn of the ventricle. There is progression of temporal and frontal lobe atrophy and associated white matter atrophy with substantial dilatation of the lateral ventricle both anteriorly and posteriorly and thinning of the corpus callosum. The basal ganglia is further degenerated, evident by a concavity of the ventricular surface.
Stage 4 (see figure 2E) cases had severe global atrophy, most notable by the dramatic loss of the basal ganglia. The ventricle is consequently concave in shape and grossly dilated. The thalamus is reduced in size, and tapered along the lateral edge. The hippocampus is extremely small and temporal cortex and white matter are almost completely atrophied, although there is some preservation of the superior temporal gyrus.
Reproducibility of staging severity.
The reproducibility of the scheme was tested using kappa statistics for multiple raters. Three independent researchers blind to case details determined the stage for each case with near perfect agreement (κ = 0.97). There was full agreement on the staging of 21 of 24 cases with discrepancies in three cases. Two of these cases were at stage 3 with one dissenting rater suggesting stage 2. In one case the temporal pole and orbitofrontal cortex was relatively well preserved (similar to stage 2) and in the other case the posterior temporal lobe was relatively well preserved (similar to stage 2). The third case was at stage 2 with one dissenting rater suggesting stage 1. In this case, the orbitofrontal cortex was well preserved. The data show that this simple scheme was reliable and reproducible for the cases examined with most cases conforming to these stages.
Case demographics and clinical indices.
For all 24 FTD cases, the mean age at death was 66 years (SD 8.7, range 51 to 89), the disease duration from diagnosis was 5.0 years (SD 3.6, range 1 to 12), and diagnosis from first onset of symptoms was 7.4 years (SD 5.0, range 2 to 18). Sixteen of 24 cases died at an advanced stage (CDR 4 or 5) with seven premature deaths (CDR 1 or 2) due to aspiration pneumonia, myocardial infarction, pulmonary embolism, or aortic sclerosis. There was also a strong correlation between duration from symptom onset and from diagnosis to death (R2 = 0.84, p < 0.0001), as may be expected. Age at death correlated with age at disease onset (R2 = 0.66, p < 0.0001). In all subsequent analyses, age at death and duration from diagnosis were used.
The clinical presentation in the vast majority of cases (17/24) was behavioral variant FTD. Two of these cases had asymmetric atrophy at the time of analysis. Of the remaining cases, three presented with FTD-MND, two with progressive nonfluent aphasia, one with semantic dementia, and one with clinical CBD. None of these cases had asymmetric atrophy at the time of analysis. The concordance between clinical and neuropathologic diagnosis is shown in table 1. Of note, the cases with movement disorders were found only in the tau-negative FTD group (see table 1).
Table 1 Concordance between pathologic diagnosis and presenting clinical syndrome
Demographic and clinical data, including dementia duration and severity, for each pathologic group are shown in table 2. The tau-positive group was on average older (72 ± 7 years vs 61 ± 7 years, p = 0.002) and had longer disease duration compared to the tau-negative group (see table 2).
Table 2 Demographic and clinical details for each pathologic group
Relationship between pathologic stage and clinical indices.
There was a correlation between disease duration and both pathologic stage (R = 0.81, p < 0.0001, figure 4A) and clinical severity (R = 0.65, p = 0.002, figure 4B). Pathologic stage also correlated with clinical severity (R = 0.71, p = 0.0007, figure 4C). There was no significant difference between pathologic groups for these relationships (see figure 4). The greatest variation in disease duration was found in patients dying with stage 3 atrophy (see figure 4A). It is evident from figure 4 that both cognitive status and the pathologic stage of atrophy worsened rapidly in the initial phase before reaching a plateau, which may last for up to 10 years (see figure 4, A and B). The increase in pathologic stage was less rapid than that observed for the CDR (see figure 4). Of note is the fact that many cases with stage 2 atrophy had very variable CDR scores (see figure 4C). This suggests a rapid clinical decline during this second stage of disease. By the time patients had reached pathologic stages 3 and 4, they invariably had advanced dementia (see figure 4C).
Figure 4. Graphs show the relationship between pathologic stage, clinical severity of disease, and duration of disease from diagnosis. Disease duration correlated with both pathologic stage (Spearman rank R = 0.81, p < 0.0001, A) and clinical severity (Spearman rank R = 0.65, p = 0.002, B). Regardless of neuropathologic group (tau-negative ▪ and tau-positive ▵), cognitive status of the patient and pathologic stage of atrophy initially declined more rapidly before reaching a plateau (A, B). Pathologic stage correlated with clinical severity (R = 0.71, p = 0.0007, C) with patients reaching end-stage cognitive change by pathologic stages 3 and 4 (C).
Discussion.
This article describes a reproducible method for staging the characteristic anatomic progression of atrophic changes in FTD syndromes. Using morphologic features and gross brain changes, individuals with FTD can be grouped into clinicopathologic stages (figure 5) akin to those devised for AD6 and HD.5 These disease stages are commonly used to understand different factors relating to disease progression. We present evidence for a similar temporal sequence of neuropathologic change in FTD. The FTD cases studied could be morphologically grouped into four progressively severe, characteristic stages of atrophy. These stages correlated with disease duration and clinical dementia severity (see figure 4). No differences in these stages were observed in patients with different underlying histopathology, suggesting a common final pathway for the neurodegeneration in FTD disorders. A previous study of patients with frontal lobe dementia and heterogeneous pathology reached similar conclusions.20 Three anatomic features in the progression of FTD atrophy are noteworthy. At death the majority of cases did not have asymmetric atrophy, suggesting that both hemispheres are fairly rapidly involved as the disease progresses, a suggestion supported by the lack of asymmetry at end stage in the cases presenting with asymmetric language or movement deficits. It should be noted, however, that our sample contained only four such cases, three of whom presented with language deficits. It will be important to verify the patterns of atrophy in a larger population of FTD cases with language presentations. Secondly, our data also suggest that the first, subtle changes in FTD occur in the orbital and superior medial frontal cortices and hippocampus. Involvement of the orbital cortex is well recognized4,21⇓ and more recent voxel-based morphometric analyses have revealed additional atrophy of the anterior cingulate and dorsolateral frontal cortices.22 Similar findings of hippocampal involvement have been reported using visual ratings of coronal MR images.23 Finally, by stage 2 there was substantial basal ganglia and white matter involvement, emphasizing that the disease process does not involve purely frontal and temporal cortices. Clinical progression to severe dementia appears to coincide with this subcortical involvement (see figure 5).
Figure 5. Drawings of half brain coronal slices show the distribution and severity of atrophy (white, none; light gray, mild; dark gray, moderate; black, severe) in FTD at stages 1 to 4 with corresponding Clinical Dementia Rating (CDR) scores. (A) Stage 1 changes are the earliest noted and appear universal at diagnosis. As may be expected, cases at this stage have mild to moderate dementia (CDR 1 to 2). Atrophy at this early stage is found mainly in the orbital and superior medial frontal cortices and hippocampus. (B) Stage 2 corresponds with a period of increasing cognitive and functional decline (CDR 2 to 4). Progression of atrophy concentrates in the orbital and superior medial frontal cortex and hippocampus with some atrophy noted subcortically (flattening of the caudate nucleus). There is mild involvement of the remaining anterior frontal cortices, temporal pole, and the posterior inferior temporal cortex. (C) By stage 3, the orbital and superior medial frontal cortices and hippocampus are extremely atrophic with little tissue remaining in these regions. Although most structures are involved at this stage, atrophy appears more severe in the temporal lobe and anterior frontal regions. The basal ganglia are concave, making the lateral ventricles appear considerably dilated. Patients at this stage have end stage dementia and have had variable duration. (D) Stage 4 is marked by gross atrophy of nearly all gray and white matter structures within these coronal slices. All cases are end stage and there is little tissue left in the basal ganglia, frontal cortex, or temporal lobe.
The progression of cognitive decline in FTD is initially rapid in comparison with the pathologic progression. The concept of early rapid decline of cognition before stabilization over time has been shown previously in large AD cohorts.24,25⇓ For example, in the majority of patients with AD, the Mini-Mental State Examination score declines from 20 to 0 over a 5-year period following diagnosis.24 The data presented in this study suggest a slightly more rapid time frame of cognitive decline in FTD. Assessment of rate of decline is hampered by the relative lack of instruments sensitive to clinical progression at the more advanced stages of dementia. As may be expected from any pathologic sample, the majority of cases in the current study were at end stage clinical disease (67%), with many institutionalized owing to the severity of their clinical illness. Likewise, patients with AD are commonly institutionalized at end stage clinical disease26-28⇓⇓ with subsequent survival dependent on their age at institutionalization (for ages 70, 75, and 80 years at entry, median survival time is 6.5, 5.5, and 4.4 years).28 At death such cases have relatively homogeneous pathology.6 In comparison, our FTD cases were younger and had longer disease duration, with gross, but variable, atrophy once the patients reached clinical ratings of very severe disease. In our sample, the period of substantial brain atrophy (stages 3 and 4) and very severe dementia (CDR of 4 and 5) seemed to last for up to 10 years (see figures 4A and 5⇑). The earliest clinical symptoms manifest at a time when many brain structures appear relatively intact, as may have been suspected from functional imaging studies.29 This is similar to observations made in AD where functional deficits are widespread30-32⇓⇓ at a time when histopathology is largely confined to the medial temporal lobe.6 There was no difference in the degree of gross atrophy between FTD cases of different pathologic types, suggesting that there may be a more unified biologic reason for the atrophy unrelated to abnormal tau deposition.
While recognizing that FTD is a complex progressive disease,2 the identification of stages of atrophy and a system for comparing different research indices should advance our understanding of this disease. The recently published consensus diagnostic guidelines for FTD2 suggest considerable heterogeneity in underlying histopathology with more homogeneity in clinical syndromes. The current scheme should provide the required framework to determine better clinical and pathologic correlates of the FTD syndromes. The use of a unified staging scheme will aid in establishing correlates relating to time and disease progression, information required in order to understand central disease processes. Although further validation of this staging scheme in other pathologic cohorts is required, the establishment of a timeframe for FTD is an important step toward the discovery of the etiologic factors leading to disease onset. The use of such stages and the refinement of this scheme for clinical settings should allow the earliest changes of FTD to be established with better certainty and scientific validity. Our research suggests that, once the reason for the slowly progressive tissue destruction in FTD is identified, more aggressive treatments at stage 1 of disease should hold considerable promise.
Acknowledgments
Supported by the National Health and Medical Research Council of Australia. C.E.S. is a Rolf Edgar Lake Fellow of the University of Sydney.
Acknowledgment
The authors thank Heidi Cartwright for the preparation of the figures.
- Received July 22, 2002.
- Accepted December 2, 2002.
References
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